The complement system provides an early acting mechanism to initiate and amplify the inflammatory response to microbial infection and other acute insults. While complement activation provides a valuable first line of defense against pathogens, inappropriate activation of complement poses potential harm to the host. For instance, the complement system has been implicated in contributing to the pathogenesis of several acute and chronic conditions, including post-cardiopulmonary bypass inflammation, myocardial infarction, stroke, acute respiratory distress syndrome (ARDS), septic shock, transplant rejection, burn injury, multiple sclerosis, myasthenia gravis, and rheumatoid arthritis. It is important to note that while complement may not be the sole cause of pathogenesis in these conditions, complement activation appears to be a major contributing factor and represents a site of therapeutic intervention. This growing recognition of the importance of complement-mediated tissue injury in a variety of disease states underscores the need for effective complement inhibitory drugs.
The complement system can be activated through either of two enzymatic cascades, referred to as the classical and alternative pathways. These pathways are shown schematically in FIG. 11. Increasing scientific evidence argues that the alternative complement pathway plays a predominant role in eliciting pathology in many acute and chronic disorders.
The classical pathway is triggered by antibody bound to a foreign pathogen, and thus requires prior exposure to the pathogen for the generation of specific antibody. There are three plasma proteins specifically involved in the classical pathway: C1, C2, and C4. In contrast, the alternative pathway is spontaneously triggered by foreign or other abnormal surfaces (bacteria, yeast, virally infected cells, or damaged tissue) and is therefore capable of an immediate response. There are also three plasma proteins specific to the alternative pathway: factors B and D, and properdin. It is important to note that both the classical and alternative complement pathways share common proteins (C3, C5-9) that are involved in the later stages of the activation cascades. The bioactive molecules produced after activation of either complement pathway include the anaphylatoxins C3a and C5a, as well as the terminal complement complex known as C5b-9, also referred to as the membrane attack complex (MAC). These anaphylatoxins initiate a cellular inflammatory response that is beneficial in the case of a pathogenic infection, but is potentially detrimental when inappropriately generated. For example, MAC causes cellular damage through its insertion into cell membranes. Like C3a and C5a, MAC can play a positive role in the destruction of pathogens, but can be deleterious when it attacks host cells.
Until recently, the role of complement activation in disease pathogenesis was poorly understood. This was due in part, to the absence of specific inhibitors that could be used to directly evaluate the role of complement in animal disease models. The development of a soluble form of the complement receptor 1 (sCR1), an inhibitor of both complement pathways, has shed light on the role complement activation plays in disease pathogenesis. The sCR1molecule suppresses complement activation by reversibly binding to the C3b and C4b subunits present in the C3-(C4b2a and C3bBb) and C5-convertases (C4b2a3b and (C3b)2Bb) of the two complement pathways. sCR1 has been demonstrated to be beneficial in animal models of inflammation, ischemia-reperfusion, transplant rejection, trauma, and autoimmune disease.
Although sCR1 is effective in inhibiting complement in vivo, it may have limitations as a therapeutic agent. Based on results from animal studies, the effective therapeutic concentration of sCR1 will be quite high. In addition, the clearance of sCR1 from the bloodstream is surprisingly rapid. Also, because sCR1 blocks both the classical and alternative complement cascades, host defense will be compromised.
Further evidence of the importance of inappropriate complement activation in disease pathology has been provided by the use of anti-C5 monoclonal antibodies. Anti-C5 antibodies have been shown to be beneficial in murine models of arthritis and immune complex nephritis. In an ex vivo model of cardiopulmonary bypass (CPB)-induced inflammation, administration of anti-human C5 monoclonal antibody inhibited leukocyte and platelet activation that normally occurs during such procedures.
Although anti-C5 antibodies have demonstrated efficacy in vivo, there are certain shortcomings of C5 as a therapeutic agent. Firstly, C5 is an abundant plasma protein (˜85 μg/ml); therefore, high concentrations of an anti-C5 monoclonal antibody would be required to block C5 activity. In addition, it is important to note that this approach would not block the formation of C3a, another potent inflammatory mediator. There is accumulating evidence that C3a can initiate potentially detrimental events, including the release of proinflammatory cytokines and prostaglandins from monocytes, histamine release from mast cells, and degranulation of eosinophils.
Available clinical data suggest that in many acute and chronic injury settings, complement activation is mediated predominantly by the alternative pathway. These findings indicate that it would be advantageous to specifically inhibit alternative pathway-mediated tissue damage in a variety of injury settings, such as post-cardiopulmonary bypass inflammation, myocardial infarction, reperfusion injury, stroke, rheumatoid arthritis, and thermal burns. This would leave aspects of the classical pathway intact to handle immune complex processing and aid in host defense against infection.
The key enzymatic step of the alternative pathway is mediated by the C3-convertase (C3bBb), which cleaves C3 to yield C3a and C3b. The alternative pathway-specific protein, properdin, has been speculated to play a role in the regulation of the alternative pathway by virtue of its ability to increase the half-life of the C3 and C5 convertase complexes (C3bBb and C3bBbC3b, respectively).
There is a need in the art for agents that reduce inflammation and other disorders that are mediated, at least in part, by the alternative complement pathway. The present invention addresses this need.
Literature
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